Alzheimers disease Target population and development of biomarkers - - PowerPoint PPT Presentation

Alzheimer‘s disease Target population and development of biomarkers

Harald Hampel Department of Psychiatry

Trinity College Dublin & University of Munich

Open regulatory issues

„AD is still an open research field“

• Which population do we study?
• How valid and reliable are biochemical markers?
• Focus on value regarding early characterisation,

detection & prediction

• Potential role for enrichment of trial populations
• Current use as endpoints in proof of concept

studies or confirmatory clinical trials

Precsymptomatic and clinical continuum of AD

IPA Expert Conference on MCI - Gauthier et al. (2006) The Lancet; PCP: Braak und Braak (1991); SMI: Reisberg und Saeed (2004); MCI: Peterson und Morris (2005)

pre-clinical phase 10-40 years subjective cognitive impairment 15 years MCI 1-5 years AD 7 years

5 -15% / yr conversion to MCI 1SD Score under memory tests in younger subjects MCI-AD conversion rate: MCI 5-15 % / yr

Alzheimer’s disease (AD)

Target population I: (mild) - moderate – (severe) AD as reference

• Clinical diagnosis: dementia syndrome and criteria for severity (mild

moderate, severe) are defined in DSM-IV-TR and in ICD-10 (F00-F03)

• Use of Screening test for degree of cogntive impairment (MMSE)
• Probablility assessment of AD: history, progressive course, exclusion of
• ther diagnosable causes of dementia
• Subtype diagnosis can be further specified using NINCDS-ADRDA criteria
• Diagnostic criteria need revision and updating:
• Sensitivity has been shown very good to excellent, specificity has been much

lower (optimised assessment and use of biomarkers)

• Revised criteria are being discussed in the APA DSM-V and WHO ICD-11

working groups

• Potential implementation of operationalised neurobiological criteria (using

laboratory methods & neurochemical information) may aid to an earlier and more accurate characterisation of AD

Hampel et al. (2008) Alzheimer‘s & Dementia; Broich (2007) International Psychogeriatrics

Alzheimer’s disease (AD) Target population II: early AD and prodromal stages

• Very early AD and prodromal stages

– MCI is proposed as a transitional stage to AD and a nosological entity in elderly patients with mild cognitive deficits – Concept is in evolution and suffers limitations: – Prevalence rates vary greatly depending on criteria used (high proportion returns to normal and up to 12%/a progress to dementia) – MCI is not considered as a homogeneous clinical entity (role of

subtypes such as aMCI and assessment tools need to be refined)

– Clinical research demonstrates that characterisation of an at risk population such as aMCI and prediction of clinical AD may be substantially supported by use of biochemical markers in the CSF & APOE genotyping – recent evidence supporting characterisation of even earlier presymptomatic at risk groups with CSF markers

Biological markers in AD

• Biomarkers can play a critical role at all stages of the drug

discovery / development process

Development of biological markers

AD presents difficulties in distinct areas (phase II-III trials)

• diagnosis (early identification of homogenous populations when

treatment would have the greatest effect - fixed marker)

• classification (enhancing specificity)
• prognosis / prediction (in trials with decline and conversion to

dementia as endpoint)

• progression (natural or pathological history)
• biological activity (mechanisms of action)
• surrogate (predicts clinical endpoints – dynamic marker)

NIH Biomarker Definitions Working Group (2001) Clin Pharmacol Hampel et al. (2008) in press

Consensus Report (1998) Neurobiol Aging

Criteria of an ideal diagnostic biomarker of AD

• detects a fundamental feature of AD pathology
• is validated in neuropathologically confirmed cases
• sensitivity > 80 % (> 85 %)
• specificity > 80 % (> 75 %)
• reliable
• reproducible
• relatively inexpensive
• simple to perform

1) Feasibility:

• validated assay
• properties including high precision & reliability
• reagents and standards well described

2) Core analyte:

• evidence of association with key mechanisms of pathology

Development of a biomarker for AD e.g. p-tau (> 15 years so far)

Stage I Stage II Stage III Description of neuropathology Identification of NFT constituents Detection of relevant p-tau epitopes Development of antibodies Assay development Correlation to neuropathology Investigation of selected patients and controls → sensitivity / specificity figures, cut-off (diagnosis vs. healthy aging, differential diagnosis, early diagnosis) Controlled diagnostic trials Stage IV Basic studies Clinical studies (diagnostic validation) Effectiveness studies

Core feasible AD biochemical CSF marker candidates

pre dic tio n, e nric hme nt, e ndpo int in trials o n e .g. BACE 1 inhibito rs

BACE1 & APP isoforms, total Aβ

key marker for tau phosphorylation state in trials, classification, prediction, enrichment

P-tau231 & P- tau181

key marker for intensity of neuronal & axonal degeneration in trials

Total Tau protein

key marker for Aβ metabolism

Aβ42

core feasible candidates function

Hampel et al. (in press)

Candidate CSF biomarker for AD: Aβ42

APP / Aβ metabolism ELISA for Aβ 1-42 Vanderstichele et al, 1998

β-sAPP γ γ -secretase SP KPI OX2 β-amyloid β-secretase C99 CTF

3D6 21F12

β-amyloid 42 1

Me an de c r e ase : 50% of c ontr

• ls

Studie s (n) 21 AD c ase s 1163 Contr

• ls

819 Me an se ns 88 % Me an spe c 87 %

10 20 30 40 50 60 70 80 90 100 G e n e t i c s L u m i n e x E L ISA - Innoge ne tic s Athe na

Blennow & Hampel (2003) Lancet Neurology; Blennow updated (2006)

Candidate CSF biomarker for AD: total tau

Blennow & Hampel (2003) Lancet Neurology; updated (2006) Hampel et al. (2008) Alzheimer’s & Dementia

Tau isoforms ELISA for total tau

N 352 N 381 N 410 N 383 N 412 N 441

HT7 AT120 BT2

Ble nnow e t al, Mol Che m Ne ur

• pathol 1995;26:231

Exon 2 3 10 10 20 30 40 50 60 70 80 90 100

Studie s (n) 52 AD c ase s 3255 Contr

• ls

1955 Me an se ns 81 % Me an spe c 90 % Me an inc r e ase : 320% of c ontr

• ls

E L ISA - Innoge ne tic s

Candidate CSF biomarker for AD: phospho tau

Studie s (n) 20 AD c ase s 1214 Contr

• ls

655 Me an se ns 81 % Me an spe c 88 % Me an inc r e ase : 300% of c ontr

• ls

10 20 30 40 50 60 70 80 90 100 P- Se r 199 P-T hr 181 T hr 231 T hr 181 +T hr 231 Se r 396 +Se r 404

Phospho tau

Formation of tangles ?

P-Thr231

Kohnken et al. (2000) Neurosci Lett

S S S S S T T T T T T S T S T S T T SS S S S S SS SS T SS SSS S

CP9 Tau1 CP27

Blennow & Hampel (2003) Lancet Neurology; updated (2006) Hampel et al. (2008) Alzheimer’s & Dementia

Comparative study: phosphorylated tau protein

diagnostic and classificatory accuracy [%] for group

comparisons (ROC-analysis)

CAC Spec Sens CAC Spec Sens CAC Spec Sens AD vs. 88 86 88 89 86 90 95 91 96

OND

81 100 77 88 91 87 97 91 98

HC

77 83 72 84 80 87 85 85 86

non-AD

p-tau 199 [fmol/ml] p-tau 181 [pM] p-tau 231 [pg/ml]

Hampel et al. (2004) Arch Gen Psychiatry

Negative predictive value: 87 % (negative test rules out AD with over 87 % probability) Positive predictive value: 76 %

European multicenter trial short-term predictive value of p-tau231 in incipient AD Text

4 centers, n: 144 - 56 HC, 88 MCI (43 conv / 45 non-conv)

Ewers et al. (2007) Neurology

Baseline analysis & short follow-up interval: 1.5 years

Prediction of conversion from MCI to AD is stable across centres using CSF P-Tau (ROC-analysis)

Ewers et al. (2007) Neurology 1 - Specificity

0.0 0.2 0.4 0.6 0.8 1.0

Sensitivity

0.0 0.2 0.4 0.6 0.8 1.0 Amsterdam Sweden Heidelberg Munich

A priori defined cut-off (27.3 pg/ml of 1 reference center) Sensitivity: 87.5% Specificity: 73.0% Classification accuracy: 80.0% Variable cut-off Sensitivity: 81.1% Specificity: 79.8 % Classification accuracy: 80.5% 4 European centers, n: 144 - 56 HC, 88 aMCI (43 conv / 45 non-conv) A priori cut-off point = 27.32 pg/ml determined based on the Göteborg center

Study design: Follow-up study over 4 - 6 years of aMCI and non-aMCI subjects MCI n= 134 57 MCI → AD 56 MCI → MCI 21 MCI → other dementias Healthy controls n= 39 cognitively stable for 3 years

T-tau > 350 pg/mL + Aβ42 / P-tau ratio < 6.5

Hansson et al. (2006) Lancet Neurol

Improving prediction of incipient AD in MCI subjects combining three core CSF biomarker candidates

Sens MCI ⇒ AD 95 % Spec MCI ⇒ MCI + other 87 %

Hazard ratio : 25.5 (7.7 – 84.9) T-tau > 350 pg / mL + Aβ42 / P-tau ratio < 6.5

Hansson et al. (2006) Lancet Neurol

Increased risk of AD in MCI subjects with pathological CSF Potential stratification & enrichment of MCI trials

BACE1 & ApoE predict conversion from MCI to AD

4.00 3.00 2.00 1.00 0.00

Follow-up interval (in yrs)

1.0 0.9 0.8 0.7 0.6 0.5 0.4 0.3

Cum Survival

Cumulative survival in ApoE & BACE model MCI converter vs. MCI Non converter follow-up 2.5 yrs

• Intitial multimodal prediction set:
• CSF: BACE1 protein, total tau, p-tau(181), abeta1-42
• Neuropsychology: free recall, recognition, naming, word fluency

(CERAD)

• ApoE genotype

Ewers et al. (accepted)

CSF core feasible biomarker candidates altered in presymptomatic and preclinical AD

• Same CSF marker phenotype as established in advanced clinical AD:
• decreased abeta42 predicts cognitive decline among older women

without MCI & dementia, Prospective Population Study; (Gustafson et

• al. (2007) J Neurol Neurosurg Psychiatry)
• aβ42 & P-Tau combination predicted later subjective cognitive

impairment & decline in quality of life in healthy elderly subjects; (Stomrud et al. (2007) Dement Geriatr Cogn Disord)

• tau/abeta42 ratio predicts later cognitive decline in non-demented

adults in a community setting (Fagan et al. (2007) Arch Neurol)

• tau/abeta42 ratio predicts later cognitive decline in normal controls at

risk for MCI (Li et al. (2007) Neurology)

Current stages of multimodal development of (bio- and imaging) markers in AD (after basic studies)

Stage I

• Methodological study
• Establishing technical

characteristics

Stage II

• Selected patients
• Determining sensitivity

and specificity

• Determining norm

values

Stage III

• Controlled dx trials

(multicenter initiatives)

• Intent to diagnose

population

• Determining prevalence

and positive/negative predictive values

• Validate norm values
• Determination of added

value of diagnostic methods (multimodal marker set)

• blood markers
• proteome analysis
• abeta oligomers
• APP isoforms
• total abeta
• ....
• BACE 1
• abeta 42/40-ratio
• abeta-Ab
• ...
• t-tau
• phospho-tau 181, 231
• abeta1-42

Conclusion: current biochemical marker research is a dynamic field

• core feasible candidates are currently beeing validated in

prospective, well controlled clinical studies

• using multi-institutional teamwork through large

collaborative groups (ADNI trials)

• already established intra-individual stability (longitudinal

CV), characteristics of the immunoassays (within-day and between-day CV)

• current validation of within-lab repeatability and between-

lab reproducibility and of multicenter diagnostic and predictive performance (sensitivity, specificity, PPV, NPV)

• multi-center validation time frame ends within next 2-5

years

Klinik für Psychiatrie und Psychotherapie Ludwig-Maximilians-Universität München

CSF biomarkers as endpoints in clinical trials on anti-Aβ compounds

Safety monitoring CSF biomarkers

• CSF poly- / mononuclear cells

General indicators of CNS inflammation

• Albumin ratio

Blood-brain barrier function / damage

• IgG index

Intrathecal IgG production IgG oligoclonal bands

• IgM index

Intrathecal IgM production IgM oligoclonal bands

• T-tau

Neuronal / axonal damage? Neurofilament protein Damage to white-matter axons? Glial fibrillary acidic protein Damage to glial cells / gliosis?

• Aβ42

Primary efficacy measure

• Aβ40

Primary efficacy measure

• ther Aβ isoforms

Optional efficacy measures

• sAPPα

Effect on non-amyloidogenic APP processing

• BACE1 act., sAPPβ

Effect on amyloidogenic APP processing

• Total tau

Downstream biomarker for effect on neurodegeneration

• Phospho-tau

Downstream biomarker for effect on tau phosphorylation

Open regulatory issues discussion: role of biochemical markers

• as the development of such biochemical markers has been

improved considerably there is still the question of how they should be used in clinical trials:

• for early characterisation, detection & prediction
• enrichment & stratification of trial populations
• endpoints in proof of concept studies or confirmatory

clinical trials

Harald Hampel Michael Ewers Arun L.W. Bokde Stefan J. Teipel Katharina Bürger University of Munich, Germany Alzheimer Memorial Center Trinity College, Dublin, Ireland